Preterm birth is a leading cause of neonatal morbidity and mortality. Many patients with preterm birth have evidence of localized intrauterine inflammation, often without an identifiable infectious etiology. The presence of intrauterine inflammation increases the risk for adverse neurological outcome in the neonate, including cerebral palsy. While there has been significant progress in recent years with respect to correlating an inflammatory state with abnormal neuronal development, the fundamental mechanisms responsible for poor neurological outcome in infants exposed to intrauterine inflammation remain unclear. Our working hypothesis is that localized intrauterine inflammation incites a maternal inflammatory response, which in turn provokes a sterile inflammatory response in the fetal brain resulting in abnormal development of the neonatal brain. To more accurately mimic what is observed clinically, we have created a mouse model of localized intrauterine inflammation. Other animal models use systemic inflammation in the mother or a direct inflammatory stimulus to the neonatal brain as the means to investigate the effects of inflammation on neuronal development. These studies are confounded by the activation of other pathways that are not inherent to localized intrauterine inflammation. Therefore, since they do not represent what occurs clinically in most cases of inflammation-induced preterm birth, they are unable to adequately discern the mechanisms and pathways responsible for adverse neurological outcome in the preterm infant. Since our model is one of localized intrauterine inflammation, we are able to investigate the signal transduction pathways and primary mediators activated in the fetus in response to localized intrauterine inflammation and the effect of the activation of these pathways in abnormal neurological development. Three specific aims are addressed in this proposal: 1) to determine if intrauterine inflammation provokes a localized, organ specific inflammatory response in fetal and neonatal brain and whether this response is mediated directly by LPS or is secondary to maternal intrauterine inflammation not involving transfer of LPS; 2) To determine if production of key maternal and fetal cytokines in response to intrauterine inflammation are the mechanisms by which an inflammatory response occurs in the fetal brain; and 3) to determine if proinflammatory mediators produced in response to localized intrauterine inflammation damage the developing fetal brain. By targeting the primary mediators and precise mechanisms involved in inflammation-induced neuronal damage, we will use our model to explore potential therapeutic options to reduce adverse neonatal outcome from exposure to intrauterine inflammation.